Signal transduction is the cascade of processes by which an extracellular signal interacts with a receptor at the cell surface to ultimately effect a change in cell functioning. Protein phosphorylation plays a key role in signal transduction. Protein phosphorylation is performed by protein kinases, and virtually all aspects of cell functioning in one way or another depend on kinase activity. Not surprisingly, then, abnormal (usually increased) kinase activity has been related to a host of diseases and disorders.
Protein kinases catalyze the transfer of phosphate from adenosine triphosphate (ATP) to specific amino acid residues (almost always a serine, threonine or tyrosine residue) of proteins. Several features of kinases make them ideally suited to function in signal transduction. One is that they often have overlapping target substrate specificities which allows “cross-talk” among different signaling pathways, allowing for the integration of different signals. A second feature is that the kinases are organized into several modular functional domains. These domains appear to have been mixed and matched through evolution to produce the large protein kinase family, and the kinases are structurally and catalytically similar. A third feature is their speed. The kinetics of phosphorylation and dephosphorylation are extremely rapid, providing for rapid responses and short recovery times, which in turn makes repeated signal transmission possible.
Given their roles in numerous diseases and in signal transduction, considerable effort has been made to develop protein kinase inhibitors. As far as is known, all of this effort has been directed at developing specific inhibitors that inhibit only a single kinase. However, the effort to find specific inhibitors of single kinases is a daunting task. Recent estimates predict the presence of greater than 2,000 protein kinase genes in the human genome. Shanley, Crit. Care Med., 30 (No. 1, Suppl):S80-S88 (2002); Cohen, Current Opinion in Chemical Biology, 3:459-465 (1999). Also, the very features described above which make kinases so useful in signal transduction, and which have made them evolve to become central to almost every cellular function, also make them extremely difficult to study and understand. U.S. Pat. No. 6,383,790. Unfortunately, the enormous number of kinases and the similarities between them have frustrated the discovery and design of specific inhibitors. U.S. Pat. No. 6,383,790. Further, because the kinase networks are highly degenerate and interconnected in unknown ways, there is considerable uncertainty with regard to which kinases should be targeted for inhibition to treat many diseases. U.S. Pat. No. 6,383,790. Moreover, it is by no means clear that a specific inhibitor of a given kinase will have any effect on a given disease. U.S. Pat. No. 6,383,790. Since kinases can be highly promiscuous, there is a significant chance that inhibiting one kinase will simply force another kinase to take its place. U.S. Pat. No. 6,383,790.
From the foregoing it is clear that it would be desirable to have methods and products for reducing unwanted phosphorylation without the need to identify specific inhibitors for individual kinases. It would further be desirable to have methods and products for the effective treatment of diseases and conditions mediated by increased phosphorylation without the need to identify specific inhibitors for individual kinases. The invention provides such methods and products.